Note that the study determined the modified-release products are sufficiently equivalent to allow patients to "switch from brand to generic formulations with little or no changes in drug plasma concentrations and thus no apparent compromise in the safety and efficacy."

Bioequivalence data from 53 studies submitted to the FDA for 25 generic modified-release drugs for epilepsy -- including phenytoin, carbamazepine, levetiracetam, and divalproex -- were reviewed. Despite considerable variability in the upper and lower bounds of the 90% confidence intervals for maximal concentrations (Cmax) and total drug exposure over time (area under the curve, AUC), the products could be interchanged without danger to patients, reported Ravi Juluru, MD, of Oak Ridge Institute for Science and Education in Nashville, and colleagues at the American Epilepsy Society's annual meeting.

In contrast, an earlier study involving immediate-release anti-epilepsy drugs -- led by Gregory Krauss, MD, of Johns Hopkins University, who was also senior investigator for the current work -- had found that patients switching among generic versions of the same drug ran significant risk of potentially dangerous increases or decreases in drug exposure.

The researchers determined the modified-release products are sufficiently equivalent to allow patients to "switch from brand to generic formulations with little or no changes in drug plasma concentrations and thus no apparent compromise in the safety and efficacy."

The FDA requires that makers of generic drugs show, through clinical pharmacokinetic studies, that blood levels of their products are close to those of the original branded forms.

Specifically, the upper bounds of the 90% CI for a generic drug's Cmax and AUC cannot exceed 1.25 of the means for the branded version, and the lower bounds cannot be less than 0.8 of the branded form's means.

For most drug classes, such variation is not a concern. But anti-epilepsy drugs have an unusually narrow therapeutic index. Particularly for immediate-release formulations, doses are usually titrated carefully to achieve seizure control without excessive side effects. If product blood levels in a given patient increase by 15%, adverse effects may result, whereas a 15% decrease may trigger onset of seizures.

In the earlier study of immediate-release anti-epilepsy drugs, Krauss and colleagues found changes in blood levels exceeding 15% could be expected for almost 40% of possible switches among the available agents.

For the modified-release drugs examined in the current analysis -- including branded forms and generics -- the variability in 90% CI for Cmax and AUC was greater than was seen in the earlier study of immediate-release products.

Despite the increased variability, there appeared to be little chance of a substantial change in values for Cmax and AUC with switches among branded and generic forms.

Differences of 15% to 25% in the upper or lower bounds of the 90% CI for Cmax and AUC from the branded form means were seen in 22.6% and 13.2% of generic products, respectively.

Juluru and colleagues noted that the general equivalence to branded forms came despite substantial variety in excipients and extended-release mechanisms.

They also reported that variability was greatest for drugs with poor solubility, again affecting the branded forms as much as generics.

The study had no external funding.

Study authors indicated they had no relevant financial interests. One author was an FDA employee.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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